Excitotoxins (Endocrine and Reproductive Disorders) --------------------------------------------------- Aspartate and glutamate are also thought to have similar neuroendocrine effects. As recently discussed by Olney (1994): "Destruction of brain neurons is not the only mechanism by which Glu[tamate] can have adverse effects on children. As described above, whenever elevated levels of Glu are present in the ciculating blood, Glu enters the endocrine hypothalamus (a CVO region which has no blood- brain barriers) and interacts with EAA [excitatory amino acids] receptors on the surfaces of hypothalamic neurons. These neurons, when stimulated by Glu or related EAA, secrete hypophysiotrophic releasing factors into the portal blood which carries the releasing factors to the pituitary where they act to trigger release of pituitary hormones into the general circulation. This phenomenon was first domonstrated in the mid 1970s (Olney 1976, Price 1978), at which time it was pointed out that repetitive exposure of immature humans to Glu throughout critical stages of development entails potential risk, even if brain damage does not occur, that hormonal biorhythms may be disturbed with adverse effects on growth and development." Carlson (1989b) showed that by administering a dose of 150 mg/kg of glutamic acid (MSG) to healthy adults (an amount which can easily be ingested by children in one restaurant meal) there was a large increase in serum concentrations of the pituitary hormones prolactin and cortisol. Carlson (1989a) tested 534 mg of aspartame in a liquid medium and and 242 mg of aspartic acid in a capsule to see if it changed prolactin, cortisol, or growth hormones outputs. He found no such changes. Carlson (1989b) also tested 10 grams of aspartic acid in capsules and found no increase in prolactin or cortisol outputs. These results were a surprise to the researchers and definately a surprise to me. It is of note, however, that capsule administration was used for aspartic acid administration (but not for aspartame). In the Carlson (1989a) experiment where 534 mg of aspartame was given (in liquid), the plasma phenylalanine did not increase significantly. This seems strange since similar amounts of aspartame administered in other experiments do raise the plasma phenylalanine levels (Caballero 1986, Burns 1991). NutraSweet funded this experiment. One wonders if the aspartame and aspartic acid were provided by NutraSweet and, if so, did they provide the "type" of aspartame which has been shown to cause large spikes in plasma aspartate levels or the "type" that does not cause this spikes (as discussed earlier). In addition, the test substances in the Carlson experiments (1989a, 1989b) were mixed with 500ml-700ml of saline solution. The subjects were also given an infusion of 9 grams of saline/liter into the antecubital vein. This was presumably done to be consistent with a previous experiment which tested prolactin stimulation by meals (Carlson 1983). Since Carlson (1989b) admits that aspartic acid metabolism may be different than glutamic acid, how can he be sure that all of these saline solutions don't affect the results for aspartic acid? Carlson should have administered aspartame in a real world type of setting, i.e., without the saline solution. What happens to prolactin and corisol measurements after meal intake is not necessarily relevant to aspartame intake because 1) the mechanism that cause excitotoxins to increase hormonal output may be different and more damaging than hormonal changes after a meal, and 2) a meal creates a number of biochemical changes and it is often the balance between these changes that prevent trouble from occurring (e.g., glucose and insulin balance), so that a single change in one parameter could be dangerous for aspartame because other key parameters are not changed. Finally, none of these studies measured levels of luteinizing hormone. Even if the hormonal levels do not change with the ingestion of aspartame (and this has yet to be confirmed with independently obtained and tested aspartame in a study without saline solution and without NutraSweet involvement), excess aspartate will likely over-excite (at least more than normal) cells in the hypothalamus and other areas of the brain not protected by the blood brain barrier. Who can say what a lifetime of such over-excitation will do to the body. Finally, it is crucial to remember that glutamic acid and aspartic acid effects are cumulative. The safety of either of these excitotoxic amino acids cannot be determined without looking at the cumulative effects. Recent animal experiments have shown that high levels of glutamate and aspartate stimulate the abrupt release of gonadotropin-releasing hormone and luteinizing hormone (Medhamurthy 1990, Goldsmith 1994). Plant (1989) and Gay (1988) have shown that an analog of glutamate, N-methyl aspartate induces the premature onset of puberty when given to monkeys repetitively. Other researchers have showed that subtoxic doses of excitatory amino acids change the sexual maturation of animals (Urbanski 1990, Lopez 1990). Subtoxic doses (i.e., less than required to cause brain lesions) of glutamate has been shown to cause a rapid elevation of leutenizing hormone in weanling and adult male rats (Olney 1976) and a depression of pulsatile output of growth hormone (Terry 1981). The dose tested in this experiment was only 25% of the toxic dose. Brann (1992) tested a dose of only 30 mg/kg of glutamate administered to female rats with low and high estrogen backgrounds. Female rats who were given estrogen showed a significant increase in the output of leutenizing hormone. Brann (1992) states: "There is a growing body of evidence which suggests that EAAs [Excitatory Amino Acids] are an integral component of the neurotransmission line that regulates gonadotropin secretion." Even the Federation of American Societies For Experimental Biology (FASEB), which usually understates problems and mimmicks the FDA party-line, recently stated in a review (FASEB 1992): "...it is prudent to avoid the use of dietary supplements of L-glutamic acid by pregnant women, infants, and children. The Existence of evidence of potential endocrine responses, i.e., elevated cortisol and prolactin, and differential responses between males and females, would also suggest a neuroendocrine link and that supplemental L- glutamic acid should be avoided by women of childbearing age and individuals with affective disorders." Aspartic acid from aspartame has a cumulative harmful effect on the endocrine system and reproductive system. Since there are few safety studies on glutamic acid suppliments, FASEB used studies relating to MSG to make this determination. While it could be argued that MSG is ingested with food and therefore does not raise the plasma glutamate level as high as with suppliments, it appears that MSG is actually more dangerous than suppliments. I have already listed a number of experiments that show large spikes in plasma glutamate from real-world MSG products -- including with full meals. I have also listed a number of experiments showing a significant spike in plasma aspartame levels from aspartame ingestion. On the other hand, glutamic acid and aspartic acid suppliments may dissolve slowly (similar to encapsulated administration) leading to the conversion of more of the amino acid to alanine and definately lessening the plasma spike of the amino acid. Excitotoxins (Pregnancy Dangers) -------------------------------- Several animal experiments have shown that excitotoxic amino acids can penetrate the placental barrier and cause damage to the fetus. Gao (1994) used a 3H-Glu tracer to show that low and higher doses of MSG injected into pregnant mice. The experiment showed that the memory and learning potential of the adult offspring was significantly affected. In addition, brain cell damage was found in both the arcuate nucleus and the ventromedial nucleus of the hypothamalmus. Fisher (1991) showed that perinatal MSG treatment of pregnant rats led to a variety of damage in the offspring including brain cell damage to the hypothalamic arcuate nucleus, parts of the circumventricular areas, parts of the visual system, and the dentate gyrus of the hippocampus. The authors stated: "The resulting hormonal dysfunction may be responsible for developmental anomalies of o rgan systems, obesity, and alterations in sensory/motor performance. We have shown that some behavioral indicators of MSG toxicity in rats can be masked by rearing them in enriched housing conditions. Here, we evaluated the impact of six housing conditions on MSG-induced alterations of organ systems and behavior. Perinatal MSG treatment reduced adrenal, heart and testes weights, as well as total white blood cell (WBC) counts, and increased tail flick latencies. .... Deficits in water maze performance were most evident following social and isolated single-case housing. We propose that deficits in water maze performance following perinatal MSG may be attributable to hippocampal damage that can be alleviated by rearing the rats in stimulating environments." Toth (1987) found that MSG given to pregnant rats caused acute necrosis of the acetylcholinesterase-positive neurons in the area postrema. The authors noticed the same effet in the fetal rats except that the "embryonal neurons were more sensitive to glutamate...." Frieder (1984) showed that damage to the offspring can occur when pregnants rats are given MSG orally as opposed to subcutaneously. Frieder administered MSG in the drinking water during the second and third trimester of pregnancy. Administering MSG led to juvenile obesity, reduced general activity levels, and a learning disability. The dosage given to the pregnant rats was quite high. However, a recent survey showed that some restaurant meals can have as much as 9.9 grams of MSG in a single dish! (UNICEF 1986) An independent study using a smaller dose of orally administered MSG and/or aspartic acid would be useful. It is important to note however, that both orally and subcutaneously administered MSG and aspartame have been shown to cause brain lesions in animals at dosages that are not emensely different. Finally, glutamate has been shown to activate certain genes (Grayson 1990). As pointed out by neuroscientist, Dr. Russell Blaylock (Blaylock 1994, page 73, 235): "The gene activation occurs via a second messenger system, inositol triphosphate and diacylglycerol, which have been activated by phospholipase C. Modification of a preexisting transcription factor induces an early response in certain genes. .... Further, this capacity to activate genes may play an important part in the plasticity of the nervous system, that is, the ability of the nervous system to adapt and change in response to the stimuli of learning and observing the outside world. This is very important, not only in the initial development of the nervous system (while the baby is in the uterus) but also much later during childhood and adolescence. This is how the various mental and motor skills develop." It seems ridiculously reckless to allow women to ingest MSG or aspartame during pregnancy since there is a chance that it will adversely and irreversibly affect the child. Perhaps that is why the FASEB (1992) committee warned pregnant women to avoid glutamic acid. Excitotoxins (Other Disorders) ------------------------------ The FASEB (1992) report, a detailed review by Nemeroff (1981), and a thoroughly-referenced analysis by Blaylock (1994) list studies which show test animals experiencing stunted growth, reproductive disfunction, changes in behavior and food intakes, obesity, reduced weights and sizes of gonads, uteri, adrenals, thyroid, and pituitary glands, changes in insulin output, and various other disorders. As opposed to the single-dose experiments showing brain lesions and changes in hormonal output, some of these experiments were long-term studies. It is beyond the scope of this review to analyze what amounts to thousands of studies involving the health effects of excitotoxic amino acids. I strongly suggest reading the reviews mentioned above to get a good overview. In 1990, Dr. John Olney reviewed the strong connection between neuropsychiatric disorders and excitatory amino acids such as glutamate and aspartate (Olney 1990a). In 1993, Altamura (1993) conducted a study measuring the plasma level of glutamate in patients with psychiatric disorders. Plasma glutamate levels were significantly higher in the patients with mood disorders, schizophrenia and organic mental disorders than in the healthy controls. One would expect that the intake of large quantities of excitatory amino acids from aspartame or MSG would only add to the problems experienced by these patients, and may have caused or contributed to their illnesses. Excitotoxins (Intake) --------------------- In the U.S., use of large amounts of free glutamic acid in the form of MSG, HVP, yeast extracts, etc. has increased tremendously over the past 15 years, especially with the advent of the low-fat craze that has swept the country (Samuels 1993). Glutamic acid is added (often in hidden forms) to low-fat foods in order to improve the taste. As much as 5,000 mg of MSG are often added to one restaurant dish. Twelve ounces of soup or broth can contain as much as 2,600 mg of MSG (Consumer Reports 1978) not counting other forms of glutamic acid added. The use of glutamic acid is increasing rapidly (Floreno 1995). It would be quite easy for a 30 kg child to ingest a restaurant meal (5,000 mg of MSG) plus 12 ounces of soup (2,600 mg of MSG) for a total intake of 7,600 mg of MSG or 253 mg/kg of MSG. The Glutamate Association tries to claim that intake of MSG in the U.S. averages only 0.5 g/day for each person. They do not account for the fact that glutamic acid intake has increased tremendously over the last 15 years and much of the intake is in "hidden" forms of MSG discussed below. Just three ounces of soup with some form of MSG would cause a person to ingest 0.5 grams of MSG. The current average is probably closer to 2 to 3 g/day and the intake at the 99 percentile is probably close to 12 to 15 g/day. Due to the public's concern about "MSG," free glutamic acid are being hidden (with the blessing of the U.S. FDA) in the labels in many ways. Common ingredients which, due to the processing technique can have a significant percentage of free glutamic acid or can have MSG directly added to them (without having to list it on the label) include (Samuels 1993): Monosodium glutamate Hydrolyzed protein Autolyzed yeast Yeast extract Yeast nutrient Yeast food Hydrolyzed oat flour Textured protein Sodium caseinate (often, but not always hydrolyzed protein) Calcium caseinate (often, but not always hydrolyzed protein) Maltodextrim Malt extract Malt flavoring Some of the industry's new favorite synonyms for MSG include: Flavoring(s) Natural flavoring(s) Natural beef flavoring Natural chicken flavoring Natural pork flavoring "Seasonings" "Spices" Due to labeling law loopholes and FDA inaction on a petition to close those loopholes (Truth 1994, Samuels 1995a), it is almost impossible for even health-conscious individuals to know whether they are ingesting MSG. A recent survey at a national restaurant convention on May 27, 1995 revealed that a number of companies which provide soups to restaurants put labels on their soups which state "No MSG Added" and/or have literature with their soup which states that there is no MSG added even though their soups contain significant quantities of added free glutamic acid (MSG). Most of the salespeople were aware of what they were doing, i.e., that their soups really had a form of MSG in it. These soups are then distributed to restaurant owners who may innocently believe and tell restaurant patrons that they contain no MSG. Therefore, when you ask a restaurant for food without MSG, you may very well get MSG unless you look at the label of the packages for MSG synonyms. Claiming "No MSG Added" on the label, but including HVP in the food product has been found "false and deceptive" by the FDA, yet no one seems to be policing restaurant products (Oliver 1991). The intake of additional excitotoxins from aspartame was discussed in an earlier section. It is important to note that only since 1987 have large amounts of aspartame been ingested (USDA 1988). Cysteine, another excitoxic amino acid is currently being added to flour as a conditioner and it is being considered by the FDA for use on produce (Samuels 1995b). Excitotoxins (Food Insdustry Arguments) --------------------------------------- The NutraSweet Company and the Glutamate Association have put together a number of arguments to try to convince FASEB, the FDA, researchers, and the general public of the "safety" of their products. Here is another excerpt from John Olney's presentation to FASEB (Olney 1993) addressing some of those arguments: Argument #1: Gutmate causes no apparent harm to children. One of the major arguments relied upon by the food industry and FDA is that immature humans do not wince or show overt signs of neurological injury when fed large amounts of glutamate as a food additive or drug. The evidence supporting this argument is that in the 1950s when glutamate was routinely fed in gram quantities to mental retardates with the mistaken believe that it might improve their IQ, these retarded children did not show obvious signs of neurological injury. Similarly "compelling" evidence was generated in an enormous, but totally uncontrolled, world-wide field experiment performed over a period of two decades by the food industry (and sanctioned by FDA) in which glutamate was routinely added to baby foods at ~ 600-800 mg per 4 1/2 Oz jar, the sole motivation being to make the baby food appealing to the maternal palate. Since hundreds of millions of immature humans thus exposed showed no obvious signs of injury, glutamate must be safe, so goes the illogic. As stated above (and I have personally witnessed this phenomenon many times), when immature animals are treated with doses of glutamate that unequivocally and irreversibly destroy neurons in the hypothalamus, they behave exactly like glutamate-fed human infants; they do not wince or show signs of discomfort or neurological injury during the acute 2-4 hour period while hypothalamic neurons are being destroyed. In some species, including primates, high doses cause emesis, but we have observed -- especially in infants -- that hypothalamic damage occurs from doses lower than those required to induce emesis. Later in life, the effects of the hypothalamic damage begin to manifest as subtle neuroendocrine deficits (obesity and disturbances in growth and sexual/reproductive function); but there is not warning of this in the behavior of the animals at the time the damage occurs. I do not comprehend how FDA and the food industry can be confident that exposure of infants and children to gluatmate in gram quantities (the practice FDA currently allows) does not silently destroy neurons in developing human hypothalamus. I know of no credible scientific evidence that could inspire confidence in that conclusion. Arguments #2 and #3: Glutamate is toxic only for newborn, and only if force-fed. An argument sometimes embraced by FDA and food industry officials, is that glutamate is toxic only for the newborn immediately after birth. A related argument is that animals will not voluntarily ingest enough glutamate to cause brain damage. Both of these arguments are easily shown to be false by the enclosed journal article (Olney 1980) which demonstrates that if weanling mice are deprived of fluids overnight, and the next morning are offered a bottle of drinking water containing added glutamate, they avidly drink enough of the glutamate solution to destroy many neurons in the hypothalamus. While the neurons were being destroyed, the mice showed no clinical symptoms other than mild somnolence. A weanling mouse is roughly comparable in developmental age to a prepubescent human child. In view of this finding, which has been confirmed by others [in aspartame] (Takasaki 1981), I must reiterate that I do not comprehend how FDA and the food industry can, with good conscience, feel confident that the glutamate intentionally being added to foods fed to human infants and children does not ever destroy hypothalamic neurons. Other food industry arguments have included: a. The spike in the plasma glutamate and aspartate levels only lasts a short time (i.e., several hours) and returns to normal quickly and therefore does not keep the levels high for long enough to do damage. Animal research using glutamic acid labelled with radioactive tracers has shown that the levels of glutamate in the brain did not peak until two hours after the blood levels of glutamate returned to normal. It was also shown that glutamate remains in susceptible areas of the brain for as long as 24 hours after the original dosing (Inouye 1976, Paull 1975). Toth (1981) found that feeding liquid diets which contained aspartic acid or glutamic acid over a prolonged period of time increase the brain tissue levels of aspartate 61% and of glutamate 35%. This is a sign that prolonged exposure to high levels of aspartic acid from aspartame or glutamic acid (MSG) may significantly affect brain chemistry over time. b. Some food and breast milk contains free glutamic acid and free aspartic acid, therefore glutamic acid (MSG) and aspartic acid from aspartame are not dangerous. This is a very popular food industry argument attempting to justify adding large amounts of excitotoxins to the food supply. There are several reasons why this is not a legitimate argument. i. The amount of free glutamic acid and aspartic acid in foods is much less than what is often found in MSG and aspartame-containing foods. The IFIC (1995) "fact" sheet lists tomatoes as containing 140 mg/100 grams of free glutamic acid. In a glutamate industry book, Giacometti (1979) also lists tomatoes as containing 140 mg/100 grams of free glutamic acid. Giacometti lists the free aspartic acid level at 35 mg/100 grams for tomatoes. These figures are based on a study by Stadtman (1972). Skurray (1988) found that fresh tomatoes contained 109 mg/100 grams of free glutamic acid. However, Skurray showed that beef soup contained 2,482 mg/100 grams of glutamic acid with MSG added. As you can see, it is very easy to ingest huge amounts of MSG from these processed junk foods. Human breast milk contains approximately 129 mg/liter of free glutamate (Giacometti 1979). This is many times less than the high concentration of gutamic acid found in MSG-containing products and much less than even the aspartic acid found in diet sodas. Despite the low body weight of infants and the corresponding high mg/kg of glutamic acid ingested per day from breast milk, the amount of glutamic acid ingested at each sitting is relatively small. Giving the regular doses of soup broth with as much as 7,000 mg/liter of glutamic acid is quite a bit different than giving the infant breast milk because the amount of MSG ingested with the soup would be dangerously high.. ii. The small amount of free glutamic acid and aspartic acid in foods is disbursed in the fiber. The food is digested gradually and the free gluatamic acid and aspartic acid are released gradually allowing these amino acids to be absorbed slowly. The food industry has been unable to show a significant glutamate or aspartate spike after the ingestion of real foods which sometimes contain small amounts of free glutamic acid or aspartic acid. A high protein meal does gradually raise plasma levels of amino acids (e.g, Stegink 1983c), but it is nothing like the plasma glutamate and aspartate spikes discussed earlier. This is key: If the free glutamic acid and aspartic acid in foods were really similar to MSG or aspartame ingestion, then these foods would cause enormous spikes in the plasma amino acid levels. Since these large spikes do not happen (Kenney 1972, Airoldi 1979), ingestion of free amino acids in foods cannot be compared to MSG or aspartame. iii. As will be discussed in the next section, persons who have regular, repeatable acute reactions to MSG (glutamic acid) generally do not react to free glutamic acid found in natural foods (Samuels 1993). c. The intake of MSG in some countries such as Thailand is very high and we do not see any health problems caused by glutamic acid in those countries. This is another popular glutamate industry claim. As pointed out by Science (1990), one cannot expect that every person in a country such as Thailand will suffer obvious adverse effects from years of excess glutamic acid. There may very well be a vulnerable subset of the population. Furthermore, I am not aware of any epidemiological studies in Thailand (or any other country) which tests for the effects of long- term MSG usage. A research team would have to compare two populations one with a high MSG intake and one with little or no MSG intake, controlling for other variables such as diet, environment, heredity, etc., and then compare the incidence of certain diseases -- especially endocrine, neurological and reproductive disorders. The glutamate industry appears to be throwing this statement out without any corroborating evidence. One might wonder why the 307 males tested in Thailand had semen analysis values that were significantly below the standard for Caucasian males (Aribarg 1986). Was it racial or is it possible that glutamate was affecting FSH, LH and prolactin outputs? In a study of 137 Thai patients, 54% of the patients with secondary amenorrhea (cessation of menstration) had hypothalamic-pituitary dysfunction (Vutyavanich 1989). Almost 40% of those who discontinued oral contraceptive steroids still experienced amenorrhea. Might MSG play a factor in the children with stunted growth studied in North-East Thailand (Chusilp 1992)? According to Rajatanavin (1993), "available data indicate a seemingly high prevalence of central hypothyroidism due to postpartum pituitary necrosis in Thailand." Could constantly over- stimulating the pituitary gland by ingesting large amounts of MSG contribute to this? Over the last 10 years there has been a significant increase in childhood obesity in Thailand (Suttapreyasri 1990, Mo-suwan 1993). One wonders if MSG, which has been shown to cause obesity in animals studies, could play a part in the increase in childhood obesity in Thailand. Fuller (1993) found that Thai women suffer from frequent reproductive system problems. Is this contributed to by long-term MSG ingestion? Animal studies found reproductive disorders in rats given glutamic acid. While this is obviously speculation, there is certainly some evidence that MSG may be contributing to illness in countries like Thailand. It is important to look closely at disease incidences before proclaiming safety. Conclusion ---------- For the following reasons, I believe that the excitotoxic effect from aspartic acid in aspartame may be a major health problem in the general population and especially in children: a. In both human and animal study experiments, the plasma aspartate level has been shown to spike to high levels after liquid administration of aspartame. b. Animals experiments in a number of different species, including rodents and primates have shown a neurotoxic effect from a single dose of MSG or aspartame. The toxic dose required is especially low in infant animals. The industry tests are flawed and border on fraudulent behavior. c. Humans are 5 times more susceptible to aspartic acid and glutamic acid than rodents and 20 times more susceptible than monkeys because they concentrate these excitatory amino acids in their blood plasma to much higher levels and for a longer period of time. Therefore, when the industry lists doses for susceptibility, dividing by 5 or 20 depending upon the species being compared is necessary. d. Single doses of aspartic acid or glutamic acid at much lower levels than that which can cause permenant brain damage has been shown to significantly affect the output of hormones in a number of difference species, including primates. Therefore, not only should one divide by 5 or 20 to determine human toxic dosage, but one should divide by at least 4 (as discussed above) to determine the single dose required to change hormonal outputs significantly in humans. Even if the dose of the excitotoxic amino acid is not high enough to cause irreversible brain lesions or excess hormonal output, regularly over-exciting unprotected brain cells day after day for months and years is a reckless practice at best, and very damaging at worst. e. In experiments conducted by independent investigators, long-term administration of glutamic acid to a variety of species have lead to obesity, stunted growth, neuroendocrine disorders, and other disorders. Despite the fact that the industry's studies have not turned up long-term danger, I am much more inclined to accept the independent studies. These repeated doses given to animals much more accurately reflects the repeated doses of excitotoxins that humans ingest. f. Excitotoxins in food have a cumulative effect. It does not make sense to consider only aspartame. Glutamic acid, aspartic acid, and possibly cysteine need to all be considered when looking at long-term safety -- or lack thereof. g. Some of the areas of the brain affected by spiked levels of aspartate and glutamate are not protected by the blood brain barrier (BBB). There are a number of conditions which can cause breaches in the BBB, leading to the possibility that other areas of the brain may be susceptible to damage or over-stimulation in certain population (e.g., old age -- see Olney (1990b)). h. I cannot see how daily spiking of the plasma glutamate and/or aspartate levels could be considered "normal" or "safe" when neuroendocrinologists are only just beginning to learn about the large role these excitatory amino acids play in the health and development of human beings. Since these excitotoxic amino acids can have such a devistating adverse effect on large populations many years after they are administered on a regular basis, adding aspartame to the food supply amounts to a very dangerous game. Once the damage is done, it will be too late and the repercussions will be felt for years after we get the junk off the market. Acute Reactions --------------- Since real-world aspartame products are such a witches' brew of small amounts of toxic and potentially toxic substances, it is difficult to be certain exactly what is causing the enormous number of acute reactions linked to aspartame. It may be a different breakdown product for different people. It may very well be a combination of two or more breakdown products acting together. Since many of the acute reactions to aspartame are the same as the acute reactions people have to MSG (glutamic acid) and since many MSG-sensitive people report the exact same reactions to aspartame (Samuels 1995a), it seems likely that the aspartic acid part of aspartame plays a role in causing these reactions. A recent comparison of a subset of MSG (glutamic acid) acute reactions with a subset of aspartame reactions revealed the following: Percent of all complaints for Symptoms MSG** Aspartame* Headache 21.0 18.4 Vomiting and nausea 8.7 6.5 Abdominal pain and cramps 4.6 4.4 Fatigue, weakness 3.2 2.6 Sleep problems 2.8 2.2 Change in vision 2.7 3.8 Change in activity level 1.6 1.1 *DHHS (1993b) **Tollefson (1988) A significant number of independent studies have confirmed that MSG can cause acute reactions (Allen 1987, Ratner 1984, Rudin 1989, Monert-Vautrin 1987, Kenney 1972, Schaumburg 1969, Ghadimi 1970). If fact, Kenney (1972) stated: "The exhibition of quantities that might properly be regarded as bizarre in the culinary setting increases the possibility of symptom occurrence, in our experience to 30% of a test population at the 5-g level." Five grams of MSG is no longer considered "bizarre in the culinary setting." The Glutamate Association has spared no expense in trying to convince the world that the large and growing quantities of excitotoxins they are dumping into the food supply are safe. It is beyond the scope of this paper to go into all of the "techniques" they have used to "prove" safety. (A look at the "research," conflict of interest in FASEB reviews, etc. reveals enough problems to give any honest researcher indigestion.) You got a taste of those techniques when looking at the excitotoxic amino acid and primate studies. I will provide an example of what they do in acute studies to hide adverse effects. But first, however, it is very important to understand that the MSG and aspartame issues are very closely tied together and therefore much of the industry hanky panky involving one of these issues is often applicable to both. Please note: a. A number of researchers are funded by both the MSG and aspartame industries and some have, not surprisingly, published glowing reviews about products. b. The glutamate industry book (Filer 1979) and the aspartame industry book (Stegink 1984a) were written by many of the same authors. c. NutraSweet is a long-time partner of MSG inventor and maker, Ajinomoto Co. of Japan. Together they are producing aspartame in France (Monsanto 1993). It is quite clear to any person but the most gullible that NutraSweet is aware of, if not an active participant, in the flawed glutamate industry experiments. The Tarasoff (1993) "study" is a typical example of glutamate industry "research." The "researchers" gave 71 healthy subjects MSG doses of 1.5, 3.0, and 3.15 grams/person over five days. The authors state that they used "a rigorous randomized double-blind crossover deisgn." They found no significant differences between the number of reactions for the MSG and the placebo. Flaws ----- 1. The "researchers" used aspartame in the beverage mixture that was given to both the test subjects and the controls. The use of aspartame (which will break down into aspartic acid among other things) has been shown to cause acute reactions similar to those caused by MSG and invalidates the entire experiment. It was revealed in a letter to FASEB from the Chairman of the International Glutamate Technical Committee (IGTC), Dr. Andrew G. Ebert, that the IGTC has been using aspartame in their beverage mixture since 1978! (Ebert 1991) Therefore, every "double-blind" experiment conducted by glutamate industry "researchers" since 1978 can be flushed down the toilet. It would take an absolute suspension of disbelief to believe that the IGTC was unaware of the similarities between glutamic acid and the aspartic acid from aspartame. In fact, on behalf of the glutamate industry, Dr. Alan Leviton testified to FASEB on April 8, 1993 that many MSG and aspartame reactions occur with similar frequencies (Samuels 1993). This deception has been going on for 13 years! Not once during that time did the "researchers" state in their publications that the beverage mixture contained aspartame! Some of the questions which arise out of this deception are: i. Were the subjects who were given the beverage mixture told that it contained aspartame so that they could give informed consent? If so, were they also told that approval to aspartame had been blocked due to the serious concern about brain cancer, uterine tumors, etc. Aspartame was not approved in liquid beverages until 1983. ii. Were persons with the genetic disorder PKU as well as pregnant PKU heterozygotes excluded from the study for their own safety? iii. Was the IGTC aware that they were using an unapproved substance in their "research"? iv. How could NutraSweet be unaware of what was going on since they must have provided the aspartame? Certainly, they knew that aspartame was not approved and its use would totally invalidate MSG experiments. v. Did the researchers know that the beverage mixture contained aspartame? I would find it difficult to beileve that they were unaware. vi. Given that this deception was not mentioned in a large number of publications, how can we believe any "research" connected with the glutamate industry? It takes an enormous amount of time to pick out all of the flaws detailed in these publications because some of them are so well hidden (e.g., monkey studies pictures discussed earlier). Knowing that some of the flaws are not even mentioned in publication after pubication makes it impossible to fully critique these articles. What future key information will be (or is being) left out of the glutamate industry- associated publications? vii. Given that this type of deception is occurring with alarming frequency (and I could cite many examples), why does it seem like the scientific community is not doing anything about it? A logical but perhaps impractical solution would be to ban all research associated with the glutamate industry or their researchers (related to MSG) and fund a series of completely corporate-neutral studies. Taking no agressive action is only encouraging more well-hidden (and some not-so-well-hidden) abuses. The glutamate industry will try to respond that they did not use much aspartame in the beverage mixture (Tarasoff 1995). Tarasoff compares the mg/kg of MSG with that of aspartame. The problem is that 1) aspartame reactions occur at much lower mg/kg doses than MSG, 2) the reactions are often similar causing there to be much less difference in placebo and test subjects, 3) many MSG-sensitive people are sensitive to aspartame and visa versa. The beverage mixture in the Tarasoff (1993) study contained nearly enough aspartame for two-thirds of a can of soda. A person who is sensitive to MSG will often react to this amount of aspartame. We have no way of knowing how much aspartame was used in the beverage mixtures of earlier glutamate industry studies. It may have been more than was used in the Tarasoff (1993) study. 2. The "researchers" excluded all persons with pre-existing conditions including general allergy syndromes, asthma, and aspirin sensitivity. Persons with allergies and especially asthma tend to have more acute reactions to excess MSG. The "general allergy syndrome" exclusion would likely exclude persons who have food insensitivities (since many people call that "allergies"). Also excluded were persons on medications and those with "other" (unspecified) conditions. While the previous flaw would tend to equalize the number of reactions that occur in the test and the control populations, this flaw would significantly reduce the number of people who experienced reactions. 3. The patient interviews occurred only two hours after consuming the MSG or placebo. It has been known for many years that reactions to MSG often occur a long time after ingestion since they are probably not typical allergic (IgE-mediated) reactions. Allen (1987) showed that asthmic reactions occur as long as 12 hours after ingestion. Dr. Alfred Scopp (1991) of the California Headache Clinic requests that his patients record all food eaten within six hours of the onset of a headache be recorded. Settipane (1987) states that the development of late onset bronchospasm (after as long as 14 hours) may be related to MSG reactions. In a review of food sensitivies, Carroll (1992) states that food sensitivies can be delayed anywhere from 2 to 48 hours. While fewer subjects would experience MSG reactions after 24 hours, a protocol that calls for only a two- hour followup is ridiculous. This would reduce the number of reactions experienced. 4. The meal given to both groups included "flavored" milk. Such products often contain a form of MSG (e.g., HVP). Why wasn't the issue of MSG in the meal addressed by the researchers? 5. Persons who experienced an aftertaste (13 people, 11 of whom took MSG, two took placebo) were excluded from the results. It is possible that persons who have more acute reactions from MSG also tend to experience an aftertaste. The aftertaste experienced may have been the result of the combination of aspartame (which often causes an aftertaste) and MSG. 6. The subjects were asked to fast before taking MSG or placebo. Fasting can sometimes precepitate a reaction caused by lowered blood sugar. Since these reactions would occur equally in the test and control groups, this would tend to reduce the significant difference between the two groups. 7. The "researchers" failed to space the test and placebo days far enough apart. This means that a person who experienced a delayed MSG reaction might do so after having switched to the control group. While Tarasoff may be able to come up with a excuses as to why their experiment (as well as other IGTC experiments) should be considered valid despite the flaws, their "research" was obviously designed to avoid finding reactions. One other common flaw in industry experiments of MSG is that they limit the kind of reactions to just a few symptoms such as those originally listed for the Chinese Restaurant Syndrome (Kwok 1968). While a few reactions were noted in 1968 by Kwok, the types of reactions that have been found to occur in people sensitive to MSG include a wide variety of reactions including neurological, respiratory, gastrointestinal, cardiac, and visual reactions (Samuels 1993). By limiting the reactions to burning, chest tightness and a couple of other reactions, researchers will often find fewer adverse reactions. The Glutamate Association is providing support for 7 or 8 new "studies" to try and prove the "safety" of MSG (Samuels 1995a). Since their deception with the use of aspartame was discovered and since the FASEB (1995) final draft report was rejected by the FDA until major modifications could be made, the IGTC was obviously trying to send as much (flawed) research to FASEB as possible before the final report was completed. This is not unlike what the glutamate industry did in the 1978-1980 FASEB "review." (Samuels 1993). FASEB is certainly in a precarious position. They recently used the MSG studies to warn a certain group of the population from the use of glutamic acid supplements (FASEB 1992). They will look extremely foolish if they now proclaim the "safety" of unrestricted use of MSG (and other excitotoxins) in the same population based on the same studies. As it turns out, FASEB (1995) foolishly did not warn susceptible individuals to avoid MSG as did FASEB (1992) even though they were aware of some of the potential dangers: "The Expert Panel concluded that the report by Carlson et al. (1989), while not definitive proof of a direct neuroendocrinological response to ingested MSG, does offer evidence for the potential for such a reaction. Consequently, this possibility must be considered plausible in the absence of contradictory evidence, particularly in light of the irrefutable evidence supplied by the animal studies of an effect of parenterally administered MSG on these hormones. The Expert Panel strongly recommends that future studies be designed to replicate and further explore this effect in humans." It is understandable that FASEB (1995) came to such a different conclusion than FASEB (1992). At least four of the members of the FASEB (1995) committee appear to have pro- glutamate industry biases. Selection of such a biased committee taints the results. It is too bad that an honest effort was not made by FASEB to select a relatively unbiased committee. One member of the FASEB (1995) committee had been found many years earlier to have a conflict-of-interest in that he received money from companies who were, I believe, members of the Glutamate Association. This person also worked as a consultant to a government department which evaluated the usefulness of MSG-containing products (Rosenthal 1976). Another member of the committee had previously been offered as a spokesperson for the "safety" of MSG by the Glutamate Association to the television show "60 Minutes" (Samuels 1995). Another member of the committee frequently worked very closely on projects with a scientist who has publically testified that MSG cannot possibly represent a hazard and who has co-edited a book for the Glutamate Association. Finally, another member of the committee is a close associate of a researcher and spokesperson for the glutamate industry. While only the first of the four inappropriate appointees may have had an "official" conflict-of-interest, the appointing of four individuals who appear to have made up their mind before the review completely skewed the results of the review. It is now quite obvious that FASEB leadership (like the FDA) can no longer be trusted to create even a marginally unbiased committee. The FASEB (1995) committee was unable to completely ignore the independent research showing acute adverse reactions to MSG, especially after discovering the abuses in the industry research. Unfortunately, the committee inappropriately stated that reactions to MSG do not occur in amounts of less than 3 grams. They based this figure on a wild guess, certainly not the experience of the countless people who react to MSG when the level is below 3 grams. Acute Reaction Studies ---------------------- Dr. Leibovitz states: "There is, at present, only one published, double- blind study that reported harmful or toxic effects of aspartame ingestion." This statement is just plain wrong. While there are not many published, double-blind studies showing adverse reactions to aspartame that is simply because there is no money available for independent researchers who want to thoroughly test aspartame. I will discuss the lack of funds in a later section. The number of published, double-blind studies which show adverse reactions to aspartame is approximately equal to the number of published, double-blind studies which were not funded by NutraSweet or organizations connected to NutraSweet. Here are a few published, double-blind studies showing adverse reactions: Camfield (1992), Van Den Eeden (1994), Walton (1993), Elsas (1988), Spiers (1988), and Koehler (1988). Kulczycki (1995) only had enough money (i.e., little funding) to study six subjects in a double- blind fashion. He discussed the results in a Letter to the Editor. Dr. Leibovitz states: "[Sensitivities to aspartame were] tested in a double-blind crossover trial in which either aspartame (30 mg/kg body weight) or placebo (cellulose) was given to 40 subjects who reported having headaches after consuming products containing aspartame." [Schiffman 1987] [NOTE: 30 mg/kg translates to about 2,100 mg for an adult; this is a very large amount that could replace about 400 g of sugar. And that's almost a pound of sugar!] Capsules were used in order to circumvent aspartame's sweet taste. There were no significant differences between groups with respect to headache, dizziness, nausea, or a host of other symptoms assessed; in other words, subjects claiming to be 'sensitive' to aspartame were unable to distinguish it from placebo in a clinical setting. These findings cast serious doubt about whether 'aspartame-sensitive' individuals actually exist." It concerns me that Dr. Liebovitz decided to give any credance to this poorly designed, NutraSweet-funded study conducted by a former NutraSweet consultant. (Susan Schiffman performed her research at the "Searle Center" at Duke University. The Searle Center is under the guidance of William Anlyan, a former G.D. Searle director. Schiffman is a former General Foods and G.D. Searle consultant. The FDA helped design the study protocol. [Gordon 1987, page 500 of US Senate 1987; Shapiro 1987, page 403 of US Senate 1987].) Dr. Liebovitz did not even mention that two much better designed studies, Koehler (1988) and Van Den Eeden (1994), show a significant increase in headaches caused by aspartame (even though fresh, encapsulated aspartame was used). Flaws ----- a. Fresh, encapsulated aspartame was used. At 30/mg/kg, encapsulating the aspartame significantly reduces the plasma amino acid spikes (Stegink 1987a) because the aspartame is absorbed gradually. b. Schiffman's study was a single day challenge while Koehler (1988), an independent investigator, conducted a thirteen-week trial. Van Den Eeden, another independent investigator, used a fairly short 7-day trial. c. Schiffman used an unspecified incentive to fly subjects to the experiment site, removing them from their normal surroundings. Since these subjects had a history of problems with aspartame, they were probably already nervous about being in an aspartame trial. Then taking these subjects out of the environment they are comfortable with and flying them to a new and different hospital environment (with a new diet and having a number of tests performed) is bound to create an atmosphere where almost anything that makes the patient nervous would cause an adverse reaction. This may account for the large numbers of adverse reactions experienced by both the test and control group. d. Removing the subjects from their environment does not allow for the researchers to assess the interaction between the environment (including other dietary factors) and aspartame ingestion. Schiffman created an environment which doesn't exist in the real world. e. Schiffman did not monitor the baseline diet or headaches unlike Koehler and Van Den Eeden. f. Schiffman did not control for known dietary triggers of headaches. Since it was a new diet designed by a dietician, maybe caffeine withdrawl or some other unknown factor play a part in so many adverse reactions. g. The subjects studied were those who reported their adverse reactions to G.D. Searle. I don't mean to sound paranoid, but I just don't trust them to make a representative selection of subjects. h. Two of the three doses of encapsulated aspartame were given with meals, further reducing the speed with which the amino acids were absorbed. i. Schiffman's protocol chose subjects on the basis that they had experienced headaches or related neurological symptoms within 24 hours after aspartame ingestion. Yet, within 12 hours after the last dose of aspartame (or 16 hours after the first dose), it would have been midnight and the subject would likely have been asleep. If some of the subjects had experienced headaches the next morning (within 24 hours of aspartame ingestion), these headaches would not have been counted because it was the washout day. Dr. Leibovitz states: "There are other well-controlled trials of aspartame that have failed to find any negative effect of aspartame--even in people who believe themselves 'allergic to aspartame.'" (Garriga 1991) The real story is that there are no well-designed studies connected with the NutraSweet company. What they've done is to flood the research community with poorly designed studies guaranteed to show that aspartame is "safe." Almost all independent looks at aspartame's pre-approval studies have shown extreme concern and recommended against approval. Almost all independent post-approval studies have shown problems with aspartame. Aspartame is a very serious problem. Anyone who has critically read the research and history of aspartame or who has taken the time to listen to some of the countless stories of severe reactions or worsening of health due to aspartame whether consumed knowingly or unknowingly would not be so quick to dismiss these adverse reactions. The Garriga study was funded by the International LIfe Sciences Institute (ILSI) which is essentially an industry annex as opposed to an independent organization as discussed in a later section. Garriga tested 12 individuals in a single blind fashion. The three positive responses were tested in a double-blind fashion and then with one diet soda. The nine negative responses were tested with one diet soda. One subject reacted twice to the diet soda, but not to the encapsulated aspartame. Flaws ----- i. Only headaches which occurred within 1 hour of exposure were considered. This is far too short, and is only useful if headaches from aspartame are allergic reactions (e.g., IgE-mediated) and not food intolerance or toxicity reactions. ii. The researchers excluded legitamate candidates for the experiment -- patients with lupus, depression, seizures, thyroid disease. Do the researchers believe that these people somehow do not have access to aspartame and therefore do not need to be tested? iii. Subject recruitment appears to be poor, at best. The fact that after a couple of years of subject recruiting attempts, they were only able to come up with 12 testable subjects only shows that they didn't know what they were doing. They could have contacted any number of groups who could have helped provide many times more candidates than they found. After a television request for subjects in 1986, Kulzycki (1995) was contacted by 88 people. One wonders how big was the ad in the Washington Post which appeared in the Volunteer/Health ad section. Is it possible that many times fewer people would see the ad as opposed to the television appeal? Also, it is important to note that the study was initiated in 1986, not long after aspartame began to be sold in carbonated beverages. In 1987, there were 600 products with aspartame, now there are over 5000 products with aspartame. It would be much easier now to find such reactors. iv. A question that needs to be asked is, "Is it possible that persons who scan the Volunteer/Health ads in newspapers are more likely to sign up for the experiment for the compensation as opposed to the test itself?" An appeal directed at everyone such as Kulzycki's television appeal or contacting patient groups where aspartame reactions are more common would be more likely to reduce this possibility. v. Three subjects had positive single-blind tests for aspartame reactions. The dosage for the double-blind test (encapsulated) was less than two-thirds the total received for the single-blind test. The dose of aspartame for the diet soda test was also too small. vi. It appears that none of the subjects were suffering from serious hypersensitivity reactions near the time of the study. One theory is that repeated exposure to a substance can lead to hypersensitivity, much like exposure to formaldehyde for example. (Coincidentally, methanol from aspartame can break down into formaldehyde.) A single dose experiment would eliminate the chance of seeing hypersensitivity develop after chronic exposure to a substance over time. Conclusion ---------- It is extremely important to understand that this study and other studies like it are only looking for hypersensitivity reactions and do not address the slow damage that can happen from long-term ingestion of aspartame. When conducting a single-dose hypersensitivity experiment, all parts of the experiment have to be conducted well -- subject recruitment, double-blind testing, proper defination of a "reaction," etc. in order to see a significant difference in reactions. It appears that the Garriga study had enough problems in those areas to significantly reduce the number of reactions that might have been found. Kulczycki (1995) was contacted by 88 individuals with hives who had seen an ad for subjects for aspartame research. Seventy-five of those subjects avoided aspartame for two weeks. Fifty of those subjects experienced a complete resolution of hives during that time. Twenty-two of these individuals who were willing to rechallenge themselves experienced skin reactions upon ingestion of aspartame. Kulczycki had only enough funding to conduct a double-blind challenge on six individuals with 50 mg. of aspartame. Four of these individuals had adverse reactions to aspartame and none had reactions to the placebo. One subject had a reaction after 3 hours, another had an immediate reaction and a delayed reaction after 12 hours, another had a reaction after 2.5 hours and delayed reactions after 9, 23, 30, and 43 hours, and the final reactor had a delayed reaction after 22 hours. These delayed reactions are not at all unusual. As pointed out earlier, Carroll (1992) states that food sensitivies can be delayed anywhere from 2 to 48 hours. Kulczycki states: "Allergists need to recognize that aspartame- induced hives can be acute, delayed, or chronic." Finally, Kulczycki pointed out a few of the flaws in another NutraSweet-sponsored study, Geha (1993). One of several flaws that were not discussed was that the dosage was very small considering encapsulated aspartame was used. Novick (1985) presented that a 22-year-old patient who had numerous deep and large nodular lesions on her legs. The patient had been ingesting a saccharin-containing drink for six years previously. Ten weeks before being presented for evaluation, the manufacturer had switched to aspartame. Within four weeks after being taken off aspartame all the lesions "spontaneously resolved without residua." Ten days after being rechallenged with 200 mg of aspartame in capsules per day, nodules reappeared on the patient's legs. After withdrawing aspartame once again, the nodules disappeared. Conclusion ---------- It is becoming increasingly clear that the most important aspect of aspartame (and MSG) studies which test for acute reactions is the funding source or loyalties of the researchers. Almost any study conducted by independent researchers and which does not commit too many obvious experimental errors will find adverse reactions to aspartame. I believe that not one study linked to NutraSweet (from now until eternity) will ever find any adverse reactions to aspartame.